Classifications

• • H—ELECTRICITY
  • H01—ELECTRIC ELEMENTS
  • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
  • H01J49/00—Particle spectrometers or separator tubes
  • H01J49/02—Details
  • H01J49/025—Detectors specially adapted to particle spectrometers
• • H—ELECTRICITY
  • H01—ELECTRIC ELEMENTS
  • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
  • H01J49/00—Particle spectrometers or separator tubes
  • H01J49/26—Mass spectrometers or separator tubes
  • H01J49/34—Dynamic spectrometers
  • H01J49/40—Time-of-flight spectrometers
  • H01J49/401—Time-of-flight spectrometers characterised by orthogonal acceleration, e.g. focusing or selecting the ions, pusher electrode

Definitions

• the signal output from each of the multipliers was electronically combined to produce a composite spectrum, wherein the signal from the first multiplier was selected for intensities corresponding to more than a single ion, and the signal from the second multiplier was selected for intensities corresponding to single ions.
• the dynamic range that was achieved was greater than a conventional detector that employed either of these modes.
• a time-of- flight mass spectrometer According to one embodiment of the present invention there is provided a time-of- flight mass spectrometer.
• a detection system comprises two or more completely separate and independently controllable detectors, each of which is coupled to separate and independent signal processing and recording electronics.
• Said detectors may consist of collection plates or anodes, which directly receive particles to be measured, such as ions in a time-of-flight mass spectrometer.
• particles to be measured are first amplified by particle multiplication means in each detector, such as a so-called channel-plate electron multiplier, the output electrons from which are collected by said collection anodes.
• Each detector may include such a multiplier that is separate and independent from the multipliers of all other detectors. Therefore, each detector may operate with a degree of amplification, or 'gain', that is different from that of all other detectors.
• Each detector may also include a so-called 'conversion dynode', which the particles to be measured first hit, and the secondary particles produced by such impacts are directed to the collection anodes, or, preferably, to the multiplier included within the detector.
• Each detector may have one or more than one collection anodes associated with it. If a particular detector has more than one collection anode, the collection anodes may be of equal collection areas, or they may be of different collection areas. The collection anodes of each detector may also be the same shape or they may be of different shapes.
• Each collection anode may be coupled to signal processing and recording electronics that is completely separate and independently controlled relative to that of any other collection anode, either within any one detector, or among the collection anodes of all detectors.
• the signal processing and recording electronics coupled to any one collector anode are separate and independent, the signal processing and recording electronics coupled to any one collector anode may be operated completely differently from any other such electronics coupled to any other collector anode, and, in fact, the electronics coupled to any one collector anode may be of entirely different technology than that of any other collector anode electronics.
• One type of the signal processing and recording electronics technology may consist, for example, of signal amplification electronics combined with a fast analog-to-digital (ADC) electronics; digital memory array in which to store a digitized spectrum and to integrate a number of digitized spectra; and a computer with associated memory arrays for processing and storage of such digitized spectra.
• Another type of signal processing and recording electronics technology may consist of, for example, signal amplification electronics coupled with signal discrimination electronics, which distinguishes signal from noise; coupled to a time-to-digital converter (TDC) electronics, which registers the flight time of ions in the ToF spectrometer in an associated histogram memory array; and a computer with associated memory arrays for processing and storage of such histogram spectra.
• TDC time-to-digital converter
• Other types and configurations of signal processing and recording electronics are also possible.
• a multiple detector arrangement is provided in which any of the detectors is provided with a single anode or multiple anodes, each anode of which is coupled to a separate TDC acquisition system.
• Single detectors with multiple-anode configurations are described, for example, in U.S. Patent # 5,777,326 for anodes of equal area, or in U.S.
• Patent # 6,229,142 for anodes of unequal areas. Such configurations extend the signal dynamic range that can be achieved with TDC acquisition systems while retaining the potentially superior time resolving power and signal-to-noise characteristics of TDC acquisition systems relative to fast ADC acquisition systems.
• the dynamic range of any one TDC acquisition system is limited to substantially less than one ion hit in any one spectrum acquisition because TDC's cannot distinguish between detector output pulses due to one ion from pulses due to the simultaneous arrival of more than one ion.
• a more practical approach is to disperse the ion flux across a wider detector area, which would allow the same number of anodes with the same detection rate, but with anodes that are larger in area and therefore more practical and economical to implement.
• One disadvantage of this approach is that a multiplier with a larger area would be required. Multipliers, such as microchannel plates, generally become prohibitively expensive to manufacture in larger sizes, and so may not be economical in many applications. Also, it is generally not possible to manufacture large microchannel plate multipliers with the same degree of flatness as smaller microchannel plates, which is important for achieving good m/z resolving power in a ToF mass spectrometer.
• a multiple detector arrangement in which the different multipliers may each contain one or a multiple number of collector anodes, each of which is coupled to a separate TDC acquisition system, may be more economical in configurations with a relatively large number of anodes, relative to a large single detector of the same effective detection area and anode number, while also providing potentially better time resolving power, due to superior detector surface flatness of multipliers with smaller dimensions, in a ToF mass spectrometer.
• a multiple-detector arrangement in which at least one of the detectors is provided with multiple anodes, each of which is coupled to a separate TDC acquisition system.
• Multiple-anode detectors are described, for example, in U.S. Patent # 5,777,326 for anodes of equal area, or in U.S. Patent # 6,229,142 for anodes of unequal areas.
• Such configurations extend the signal dynamic range that can be achieved with TDC acquisition systems while retaining the potentially superior time resolving power and signal-to-noise characteristics relative to fast ADC acquisition systems.
• the number of anodes that can be employed within practical and/or economical restrictions nevertheless limits the dynamic range achievable with such multiple-anode TDC configurations.
• multiple-anode TDC configurations require that the clocks or timers of all TDC electronics be synchronized to a precision at least as good as the precision of the clocks; otherwise, the overall time resolution of the resulting spectrum will be degraded.
• Such time synchronization becomes increasingly more difficult as the number of TDC systems increases.
• each set of TDC electronics adds additional cost to the system, so the multiplicity of anodes and TDC acquisition systems may be limited by economical considerations.
• the number of multi-anode TDC systems is limited to a practical, economical number, and at least one other detector is employed to measure and record ion signal amplitudes in parallel with the TDC measurements using a fast ADC and associated electronics system.
• This at least one other detector may be operated with a lower multiplier gain which allows accurate measurement of a range of signal amplitudes that overlaps with, but extends to much greater signal amplitudes than, the dynamic range of the detector or detectors with the multiple anodes and TDC acquisition systems. Therefore, such a multiple-detector combination according to this embodiment of the present invention provides substantially greater dynamic range, than that of prior art practical, single detectors with either multiple anodes and TDC acquisition systems, or with a single anode and an ADC acquisition system.
• such a multiple-detector combination provides substantially better time resolving power and signal-to-noise, as discussed above, compared to that of prior art single detectors with either multiple anodes and TDC acquisition systems, or with a single anode and an ADC acquisition system.
• This detector within the range of the ADC, may measure signal amplitudes accurately, while time information may be measured more precisely for these signals by the TDC acquisition system(s).
• At least one other detector in these particular embodiments of the invention may be configured with at least one anode.
• one anode of the at least one other detector is coupled to a separate fast ADC acquisition system.
• the gain of the multiplier of each of these at least one other detector may be optimized for the signal amplitude range not completely included within the range of other detectors.
• the dynamic range of the composite spectrum which results from combining the spectra from each ADC acquisition system, is therefore greater than would be possible with prior single detection systems.
• a multiple detection system that consists of at least two separate and independently controlled detectors, each of which includes a single collector anode coupled to a separate and independently controlled fast ADC and associated signal processing and recording electronics.
• the gain settings of each detector may be optimized for different ranges of signal levels, for example, one detector and amplifier may be optimized for the most intense ion signals, while the gain settings of at least one other detector and amplifier may be optimized for less intense ion signals, and/or the gain settings of one other detector and amplifier may be optimized for single ion signals.
• a multiple detection system that consists of at least two separate and independently controlled detectors, where each detector may contain one or more collector anodes.
• Each anode of each detector is coupled to a separate and independent amplifier, each of which may provide a different gain or signal amplification.
• the outputs of such amplifiers from at least one detector may then be coupled to separate and independently controlled fast ADC acquisition systems.
• the outputs of the amplifiers coupled to other anodes associated with other detectors may also be coupled to separate ADC systems, and/or, to separate TDC acquisition systems.
• One situation in which this embodiment of the present invention is advantageous is when the signal dynamic range of a detector configured with multiple anodes exceeds the dynamic range of the ADC acquisition systems.
• the population of particles comprising each spectrum to be measured may be distributed homogeneously and simultaneously across all, or any subset of, detectors.
• One preferred method of achieving homogeneous spatial dispersion across multiple detectors is to pulse accelerate a homogeneous spatial distribution of ions from the pulse acceleration region of an orthogonal acceleration ToF mass spectrometer, which injects a segment of a homogeneous ion beam into the flight tube.
• a less preferred method of achieving a spatial dispersion of ions across multiple detectors is to allow an initial population of ions pulse accelerated into a ToF mass spectrometer to disperse spatially as they traverse the ToF mass spectrometer, for example, due to initial kinetic energy variations in the initial ion population, or due to scattering effects in the ToF optics such as from grids, gas molecules, electric field inhomogeneities, etc.
• the result is that the collection of ions is distributed homogeneously across both detectors of a dual- or multiple- detector arrangement for any particular spectrum acquisition; therefore, the signal from either detector is representative of the relative abundance of different m/z ions in the sampled ion population.
• a collection of ions that is pulse accelerated into an orthogonal acceleration ToF mass spectrometer is arranged to develop a spatial distribution that depends on the ion mass-to-charge (m/z).
• An m/z-dependent spatial distribution along the axis of the initial ion beam entering the pulse acceleration region of an orthogonal acceleration ToF mass spectrometer may result, for example, from direct sampling of the ion population emanating from a supersonic expansion.
• the velocity distributions of ions of all m/z values are similar in such a supersonic expansion, so larger m/z values will travel a greater distance along the initial ion beam axis in the direction of the detector region because they take longer to traverse the ToF spectrometer.
• Another preferred method of achieving an m/z-dependent spatial distribution of ions in the initial ion population is to pulse extract ions over a short time period from an ion source or an ion storage region and to direct them into the pulse acceleration region of an orthogonal acceleration ToF mass spectrometer.
• the pulse extraction of ions from such ion populations causes all extracted ions to acquire the same nominal kinetic energy.
• ions of greater m/z values travel slower than lighter m/z ions, resulting in a m z separation in the ion beam by the time the ion population fills the ToF pulse acceleration region and is pulse accelerated into the ToF mass spectrometer.
• the dispersion of different m/z values along the initial extracted ion beam axis continues as the ions traverse the ToF flight tube, so that ions of lower m/z values arrive at the detector region farther away from the pulse acceleration region than ions of larger m/z values.
• a multiple-detector arrangement in which one or several detectors is positioned to detect ions of lower m/z values of an ion population dispersing in the initial ion beam direction, as described above, while the second and/or subsequent detector(s) may be located so as to detect ions of greater m z values.
• a single detector of the prior art may, in principle, be large enough to cover the same area, hence the same m/z range as two or more smaller detectors, but, because the cost of detectors generally increases dramatically with their size, it is usually more cost effective to provide two or more smaller detectors to provide the same detection area as one large detector.
• Another significant advantage of the multiple detector arrangement of the present invention is the flexibility which a multiple-detector arrangement provides to optimize the detection and measurement of ions in the different segments of the m/z spectrum that arrive at the two or more different detectors. For example, the intensities of ions of larger m/z values are often lower than the intensities of ions of smaller m/z values.
• the detector that receives the larger m/z ions may be operated with a larger gain, and/or may be coupled to a single or multi-anode TDC if the intensities are low enough, in contrast to the detector(s) that receives the greater intensity, lower m/z ions, which may require a relatively low gain, and/or a fast ADC, because of their greater intensities.
• the generally lower-intensity, higher m/z ions may be measured with better signal-to-noise with the multiple detector arrangement of the present invention than with the prior art single detector configurations in which the operating conditions were constrained in order to accommodate the lower m/z ions, as well as the high m/z ions.
• ions will travel a greater distance along a direction orthogonal to the axis of the ToF acceleration axis, and the ions will arrive at the detector region farther away from the pulse region than lower energy ions. Therefore, by properly adjusting the kinetic energy of the ions prior to their pulse acceleration into the ToF analyzer, they can be made to arrive at one detector or another, provided that the detectors are separated in space along the initial ion beam axis.
• the signals at the anodes of every detector may or may not be measured and/or recorded by the respective signal processing and acquisition systems simultaneously.
• signals from each anode may be recorded simultaneously for each spectrum.
• the signals from some or all of the anodes from some or all detectors of a multiple-detector arrangement may instead be processed and recorded alternately, that is, the signals from one anode may be recorded and perhaps integrated over some period of time, and then the signals from another anode may be processed and recorded for some period of time, and so on for the signals at other anodes.
• this alternate method of measuring m/z spectra is sufficient, other preferred embodiments of the present invention may be advantageous with respect to cost and complexity.
• the signals from each of the collector anodes may be routed through a common signal processing electronics and a common signal recording electronics.
• any amplifiers in the signal pathways may nevertheless be changed to different values from the recording of signals from one anode to the subsequent recording of signals from another anode.
• the signals from each of these anodes may be processed by their separate and independently controlled signal processing electronics, with possibly different amplifier gains, and then routed via fast analog switches to a common signal recording electronics.
• the primary advantage of these preferred embodiments is reduced cost and complexity, because multiple electronics systems that are redundant from one anode to another are eliminated by such signal multiplexing from one anode to another.
• the number of spectra that are accumulated to produce a net integrated spectrum from each anode of a multiple-detector arrangement may be different for each detector.
• a detector and associated electronics that is optimized to record low intensity signals may integrate a greater number of spectra than the detector and associated electronics of the other detector which is optimized for signals with greater intensities.
• the total integration time is divided between the two detectors, a better signal-to-noise is achieved than if each detector integrated the same number of spectra.
• FIG. 1 is a diagram of one embodiment of the invention, comprising a hybrid orthogonal pulsing ToF mass analyzer configured with an Electrospray ion source, an ion guide and transfer optics, and a dual detector system, in which an ion population is distributed between the two detectors of the dual detector system.
• FIG. 2 is a diagram of one embodiment of the invention, comprising a hybrid orthogonal pulsing ToF mass analyzer configured with an Electrospray ion source, an ion guide and transfer optics, and a dual detector system, in which an ion population is directed to impact one detector of a dual detector configuration, or the other detector, exclusively.
• FIG. 3 is a diagram of one embodiment of the invention that illustrates a dual detector arrangement consisting of two separate and independent detectors, each comprising a dual microchannel plate multiplier assembly and a collector anode, where one detector is coupled to a fast ADC signal processing and recording electronics, and the other detector is coupled to a time-to-digital converter signal processing and recording electronics.
• FIG. 4 is a diagram of one embodiment of the invention that illustrates a dual detector arrangement in which both detectors are coupled to separate fast ADC signal processing and recording electronics.
• FIG. 5 is a diagram of one embodiment of the invention that illustrates a dual detector arrangement in which each detector is coupled to separate fast signal amplifier electronics, the outputs of which are routed to the inputs of a fast analog switch.
• the switch selects the amplified analog signal from one detector or the other to be digitized by a single ADC electronics.
• a memory array stores and integrates multiple spectra from one detector or the other before transferring the integrated spectrum to computer memory.
• FIG. 6 is a diagram of one embodiment of the invention that illustrates a dual detector arrangement in which each detector is coupled to separate fast signal amplifier electronics, the outputs of which are routed to the inputs of a fast analog switch.
• the switch selects the amplified analog signal from one detector or the other to be digitized by a single ADC electronics.
• a memory array stores and integrates multiple spectra from one detector while another memory array stores and integrates multiple spectra from the other detector.
• FIG. 7 is a diagram of one embodiment of the invention that illustrates a dual detector arrangement in which each detector is coupled to separate inputs of a fast analog switch.
• the switch selects the signal from one detector or the other to be routed to a single amplifier and/or other signal processing electronics before the amplified signal is digitized by a single fast ADC electronics.
• FIG. 8 is a diagram of one embodiment of the invention that illustrates a dual detector arrangement in which one detector containing a single collector anode is coupled to a fast ADC electronics, while the other detector contains multiple collector anodes, each of which is coupled to a separate TDC electronics. All of the TDC electronics share the same histogram memory.
• FIG. 9 is a diagram of one embodiment of the invention that illustrates a dual detector arrangement in which one detector contains two collector anodes, one of which is coupled to ADC electronics, and the other of which is coupled to TDC electronics including a separate histogram memory array; and in which the other detector contains multiple anodes, one of which is coupled to ADC electronics, and all the others of which are each coupled to separate TDC electronics, but which share a common histogram memory array.
• FIG. 10 is a diagram of one embodiment of the invention that illustrates a triple detector arrangement in which one detector containing a single collector anode is coupled to a fast ADC electronics; and in which a second and third detector each contains two anodes, each of which are each coupled to separate TDC electronics, but all of which share a common histogram memory array.
• FIG. 11 is a diagram of one embodiment of the invention that illustrates a triple detector arrangement in which one detector containing a single collector anode is coupled to a fast TDC electronics; and in which a second and third detector each contains two anodes, each of which are coupled to separate TDC electronics; and in which all TDC electronics from all detectors share a common histogram memory array.
• Time-of-Flight (TOF) mass analyzers that incorporate a linear or an orthogonal pulsing region as a means for pulsing ion bunches into the ToF tube are well known to those skilled in the art.
• Orthogonal pulsing Time-of-flight (O-TOF) mass analyzers are typically configured with the ion source located external to the TOF pulsing region. The primary beam of ions exiting an ion source is directed into the pulsing region of the TOF with a trajectory oriented substantially orthogonal to the axis of the Time-of-flight tube drift region.
• Several types of ion sources can be interfaced with orthogonal pulsing Time-of-flight mass analyzers.
• Electron lonization El
• Chemical ionization CI
• Photon and Multiphoton Ionization FAB
• FAB Fast Atom Bombardment
• LD Laser Desorption
• MALDI Matrix Assisted Laser Desorption
• TS Thermospray
• API Atmospheric Pressure Ion sources
• ES Electrospray
• APCI Atmospheric Pressure Chemical Ionization
• ICP Inductively Coupled Plasma
• Ions can be delivered to the time-of-flight orthogonal pulsing region from several mass analyzer types including but not limited to multipole ion guides including quadrupoles, hexapoles or octopoles or combinations thereof, triple quadrupoles, magnetic sector mass analyzers, ion traps, time-of-flight, or Fourier transform mass analyzers.
• mass analyzer types including but not limited to multipole ion guides including quadrupoles, hexapoles or octopoles or combinations thereof, triple quadrupoles, magnetic sector mass analyzers, ion traps, time-of-flight, or Fourier transform mass analyzers.
• Hybrid or tandem instruments allow one or more steps of mass to charge selection or mass to charge selection with fragmentation (MS or MS/MS n ) combined with orthogonal pulsing Time-of- flight mass analysis.
• Ions may be pulsed directly into the drift region of the time-of-flight mass spectrometer, or they may be trapped and accumulated for some period of time, and/or undergo collisional fragmentation, in the pulsing region due to the action of a pseudo- potential well that may be incorporated in the pulsing region, as described in co-pending application by the same inventors, titled "Charged Particle Trapping in Near Surface Potential Wells".
• Ions that are pulse accelerated into the ToF drift region may arrive directly at a detector region, where they are detected and recorded. This configuration is commonly referred to as a "linear ToF mass spectrometer".
• the ions may be reflected by an electrostatic mirror, well-known to those skilled in the art and commonly referred to as a "reflectron” mirror, after traversing the drift region. Upon reflection in the mirror, the ions then traverse the drift region again before arriving at the detector region.
• This configuration of a time-of-flight mass spectrometer is commonly referred to as a "reflectron ToF mass spectrometei
• One preferred embodiment of the invention is the configuration of an orthogonal Time-of- flight mass spectrometer that incorporates a multiple-detector arrangement for detecting and recording the intensities and arrival times of ions at the end of their flight through the spectrometer, as shown in FIG.
• FIG. 1 is a diagram of an orthogonal pulsing ToF mass analyzer that incorporates two dual detector arrangements: one dual detector arrangement that includes detectors 22 and 23, and the other dual detector arrangement that includes detectors 50 and 51. Although two dual detectors are illustrated in FIG. 1, either or both of the dual detector arrangements could just as well be detector arrangements consisting of three or more detectors.
• the hybrid orthogonal ToF mass spectrometer depicted in FIG. 1 is also configured with an Electrospray (ES) ionization source and a multipole ion guide ion trap.
• ES Electrospray
• the multipole ion guide that extends continuously into multiple vacuum pumping stages can be operated in RF only, mass-to-charge selection or ion fragmentation mode as described in U.S. Pat. Nos. 5,652,427; 5,689,111; 6,011259; and 5,962,851.
• the instrument diagrammed can be operated in MS or MS/MS" mode with gas phase collisional induced dissociation (CID).
• CID gas phase collisional induced dissociation
• Electrospray ion source 2 four vacuum pumping stages 3, 4, 5 and 6 respectively, multipole ion guide 8 that extends into vacuum pumping stages 4 and 5, orthogonal ToF pulsing region 10 including pusher electrode 11 with pusher electrode surface 12, ToF drift region 20, single stage ion reflector or mirror 21 and detectors 22 and 23, and detectors 50 and 51.
• Liquid sample bearing solution is sprayed into Electrospray source 2 through needle 30 with or without pneumatic nebulization assist provided by nebulization gas 31.
• the resulting ions produced from the Electrospray ionization in Electrospray chamber 33 are directed into capillary entrance orifice 34 of capillary 35.
• the ions are swept though capillary 35 by the expanding neutral gas flow and enter the first vacuum stage 3 through capillary exit orifice 36.
• a portion of the ions exiting capillary 35 continue through skimmer orifice 37 and enter multipole ion guide 8 at entrance end 40 located in the second vacuum pumping stage 4.
• Ions exiting ion guide 8 pass through orifice 43 in exit lens 41 and through orifice 44 of focusing lens 42 and are directed into pulsing region or first accelerating region 10 of ToF mass analyzer 45 with a trajectory that is substantially parallel to the surface of planar electrodes 11, 12 and 13.
• the surfaces of planar electrodes 11, 12 and 13 are positioned pe ⁇ endicular to the axis of ToF drift tube 20.
• Pusher electrode surface 12 is configured as part of pusher electrode 11 and counter or ion extraction electrode 13 is configured with a high transparency grid through which ions are accelerated into ToF drift region 20.
• the gap between pusher electrode 11 with pusher surface 12 and counter electrode 13 defines the orthogonal pulsing or first accelerating region 10.
• a substantially neutral or zero electric field is maintained in pulsing region 10 during the period when ions are entering the pulsing region from multipole ion guide 8.
• an accelerating field is applied between electrodes 11 with surface 12 and electrode 13 to accelerate ions into ToF tube drift region 20.
• the appropriate voltages are applied to lenses 11, 13, 14, steering lenses 15 and 16, flight tube 17, ion reflector electrodes 19, post accelerating grid 18 and detectors 50 and 51 to maximize ToF resolving power and sensitivity.
• Ions pulsed from the ToF first accelerating region 10 may be directed to impact on detectors 22 and 23 or detectors 50 and 51 depending on the analytical result desired.
• the pulsed ion beam is steered with steering lenses 15 and 16, detectors 22 and 23 or detectors 50 and 51 can be tilted as is described in U.S. Pat. No. 5,654,544 to achieve maximum resolving power.
• the original ion population produced by Electrospray ionizaton may be subjected to one or more mass selection and/or fragmentation steps. Ions may be fragmented through gas phase collisional induced dissociation (CID) in the capillary skimmer region by applying the appropriate potentials between the capillary exit electrode 39 and skimmer 38.
• CID gas phase collisional induced dissociation
• the analytical steps of ion trapping and/or single or multiple step mass to charge selection with or without ion CID fragmentation can be conducted in multipole ion guide 8 as described in U.S. Pat. No. 5,689,111 and U.S. patent application Ser. No. 08/694,542.
• Said mass selection and CID fragmentation steps are achieved by applying the appropriate RF, DC and resonant frequency potentials to rods or poles 7 of multipole ion guide 8.
• a continuous or gated ion beam of the resulting ion population in multipole ion guide 8 can be transmitted into ToF pulsing region 10 from ion guide 8 through lens orifices 43 and 44 in electrodes 41 and 42, respectively.
• a segment of the ion beam between 60 and 61, traversing the orthogonal acceleration region 10, is pulse accelerated into the ToF drift region 20.
• the ion beam segment defined by end points 60 and 61 traverses the drift region, is reflected in the reflectron 21, and traverses the drift region 20 again before arriving at the detectors 50 and 51.
• the trajectory followed by the ion beam segment is illustrated in FIG. 1 by the trajectory paths 52 and 53 for the end points 60 and 61, respectively. All ions within beam segment between end points 60 and 61 follow trajectories between and substantially parallel to trajectories 52 and 53 through the time-of-flight mass spectrometer regions. As illustrated in FIG.
• an ion beam segment centered at 60 may be directed to impact detector 50 entirely, or may be directed to impact detector 51 entirely.
• the ion beam segment centered at 60 traverses the various regions of the ToF mass spectrometer as indicated by the trajectory line 52 in order to impact detector 50, or as indicated by the trajectory line 53 in order to impact detector 51.
• the ion beam segment centered at 60 is directed to impact detector 50 or detector 51 by electrostatic deflection in the field between deflector electrodes 15 and 16. In conjunction with such steering, detectors 50 and 51 can be tilted as is described in U.S. Pat. No. 5,654,544 to achieve maximum resolving power.
• deflection of charged particles may also be accomplished by magnetic deflection fields, or by a combination of electrostatic and magnetic deflection fields. Any such deflection field-generating devices and methods are included within the scope of the present invention.
• optical deflection devices and methods may be used, such as mirrors, lenses, prisms, and the like, and such optical devices and methods are also included within the scope of the present invention.
• the gain of amplifier 70 is controlled by a reference voltage from gain control supply 72 provided at the gain control input 71 of amplifier 70.
• the amplified signal at the output of the amplifier 70 is provided to the input 73 of a fast analog-to-digital converter 78, which converts the analog signal to a sequence of digital values corresponding to the amplitude of the signal as a function of time.
• the array of digital values therefore represents the ion flux arriving at the detector 50 as a function of time, which is easily interpreted as the m/z spectrum of ions in the ion population.
• a number of such spectra may be integrated in integrating memory 80, in order to improve the signal-to-noise and intensity dynamic range of the spectrum, before being transferred to the memory of computer 101 for digital processing.
• detector 51 consists of a dual channel electron multiplier plate assembly 83, which is comprised of two channel electron multiplier plates 84 and 85 in series, so that, in response to the impact of ions 53, the first plate 84 produces an amplified output current which is further amplified by the second plate 85.
• An anode 87 collects the output current 86 of the second microchannel plate electron multiplier 85.
• the gain of the multiplier assembly is controlled by the voltage differential applied between the front surface of plate 84 and the back surface of plate 85. This voltage differential is provided by power supply 88.
• the output current 86 collected by anode 87 flows to the input 89 of amplifier 90.
• the gain of amplifier 90 is controlled by a reference voltage from gain control supply 92 provided at the gain control input 91 of amplifier 90.
• the amplified signal at the output of the amplifier 90 is provided to the input 93 of a discriminator 94, which compares the amplitude of the signal at input 93 with the amplitude of a reference level provided at threshold reference input 95, which is adjusted by threshold reference adjustment supply 96. If the amplitude of the signal at input 93 is greater than the amplitude of the reference level at threshold reference input 95, then the discriminator 94 produces an output pulse, which is provided to the input 97 of a time-to-digital converter (TDC) 98. If the amplitude of the signal at input 93 is less than the amplitude of the reference level at threshold reference input 95, then the discriminator 94 produces no output pulse, which is also sensed at the input 97 of the TDC 98.
• TDC time-to-digital converter
• the TDC continually senses whether a pulse has occurred at each increment or cycle of a clock or timer. If the discriminator produces a pulse at any clock cycle, the time of the pulse relative to some start time is registered, and the corresponding time bin in a histogram memory a ⁇ ay is incremented by one.
• the start time of the clock typically corresponds to the time of pulse acceleration of the ions into the ToF drift region, so the time recorded by the TDC corresponds to the flight time of ions in the ToF mass spectrometer.
• a number of such spectra are typically integrated in histogram integrating memory 100 to produce a histogram corresponding to an average ToF spectrum, before the spectrum is transferred to the memory of computer 101.
• the spectral information from both detection systems may be integrated in the computer 101 in real time during data acquisition, or after data recording, to produce a composite integrated spectrum. Because each detector 50 and 51 may be operated completely independently and simultaneously within the time of a spectrum acquisition, the operation of each detection system may be optimized separately with respect to signal-to-noise and dynamic range. For example, the TDC detector 51 may be operated with high gain as controlled by multiplier differential power supply 88, and the output signal from detector 51 combined with a discriminator 94 to achieve better signal-to-noise for the detection of single ion 'hits' than with a fast ADC for some m/z values.
• the fast ADC detector 50 may be operated at a lower gain, as set by the multiplier differential supply 68, than would typically be employed because it would no longer be required to efficiently detect single ion hits.
• Operating the fast ADC detector 50 with a lower gain may allow the detector 50 to operate with a signal linear dynamic range that extends to greater maximum signal levels, while maintaining a linear response, than if it were operated with the higher gain necessary to detect single ion hits with good efficiency.
• the spectrum resulting from the integration of the TDC spectrum of single ion hits from detector 51 and the ADC spectrum of simultaneous multiple-ion hits from detector 50 may exhibit a greater dynamic range and signal-to-noise than would be possible with the prior art of only one of these detection systems.
• the spectra originating with detector 51 may be processed to extract information of interest regarding the relatively low intensity signals, while the spectra originating with detector 50 may be processed to extract information of interest regarding the relatively high intensity signals.
• the information of interest may therefore be obtained from the multiple detector system without first forming, or, indeed, ever forming, a so-called composite spectra from the separate spectra.
• the separate spectra may, in any case, be maintained and stored separately.
• ion arrival times may be measured with greater precision and accuracy with a TDC than with typical fast ADCs, resulting in improved m/z ToF resolving power and measurement accuracy for those low-intensity ions in the resulting integrated spectrum.
• the greater time precision of the TDC approach may provide better arrival time information for the simultaneous arrival of multiple ions at other m/z values than the fast ADC.
• amplitude information may be provided by the fast ADC detection system, while the arrival time information for all m/z values as measured by the TDC detection system is used to enhance the precision and accuracy of the measured m/z values.
• this aspect of the present invention allows the multiple-ion amplitude information from the ADC to be combined with the more precise arrival time information and better signal-to-noise of the TDC, the result being that m/z ToF spectra may be produced with greater dynamic range, time resolution, and signal-to-noise than is possible with the prior art detection systems.
• FIG. 4 illustrates only two detectors configured this way, it should be understood that any number of detectors may be configured similarly within the scope of this embodiment of the present invention, including multiple detectors coupled to separate ADC electronics, as well as other detectors coupled to TDC electronics.
• detector 50 consists of a dual channel electron multiplier plate assembly 63, which is comprised of two channel electron multiplier plates 64 and 65 in series, so that, in response to the impact of ions 52, the first plate 64 produces an amplified output current which is further amplified by the second plate 65.
• An anode 67 collects the output current 66 of the second microchannel plate electron multiplier 65.
• the gain of the multiplier assembly is controlled by the voltage differential applied between the front surface of plate 64 and the back surface of plate 65. This voltage differential is provided by power supply 68.
• the output current 66 collected by anode 67 flows to the input 69 of amplifier 70.
• the gain of amplifier 70 is controlled by a reference voltage from gain control supply 72 provided at the gain control input 71 of amplifier 70.
• the amplified signal at the output of the amplifier 70 is provided to the input 73 of a fast analog-to-digital converter 78, which converts the analog signal to a sequence of digital values corresponding to the amplitude of the signal as a function of time.
• the array of digital values therefore represents the ion flux arriving at the detector 50 as a function of time, which is easily interpreted as the m/z spectrum of ions in the ion population.
• a number of such spectra may be integrated in integrating memory 80, in order to improve the signal-to-noise and intensity dynamic range of the spectrum, before being transferred to the memory of computer 101 for digital processing.
• detector 51 in FIG. 4 consists of a dual channel electron multiplier plate assembly 83, which is comprised of two channel electron multiplier plates 84 and 85 in series, so that, in response to the impact of ions 53, the first plate 84 produces an amplified output current which is further amplified by the second plate 85.
• An anode 87 collects the output current 86 of the second microchannel plate electron multiplier 85.
• the gain of the multiplier assembly is controlled by the voltage differential applied between the front surface of plate 84 and the back surface of plate 85. This voltage differential is provided by power supply 88.
• the output current 86 collected by anode 87 flows to the input 89 of amplifier 90.
• the gain of amplifier 90 is controlled by a reference voltage from gain control supply 92 provided at the gain control input 91 of amplifier 90.
• the amplified signal at the output of the amplifier 90 is provided to the input 173 of a fast analog-to-digital converter 178, which converts the analog signal to a sequence of digital values corresponding to the amplitude of the signal as a function of time.
• the array of digital values therefore represents the ion flux arriving at the detector 51 as a function of time, which is easily interpreted as the m/z spectrum of ions in the ion population.
• a number of such spectra may be integrated in integrating memory 180, in order to improve the signal-to-noise and intensity dynamic range of the spectrum, before being transferred to the memory of computer 101 for digital processing.
• the spectral information from both detection systems may be integrated in the computer 101 in real time during data acquisition, or after data recording, to produce a composite integrated spectrum.
• the gain of multiplier 63 of detector 50 may be adjusted by adjusting multiplier differential supply 68 to a low enough value to ensure that the greatest number of simultaneously arriving ions within a m/z spectrum does not produce a multiplier output signal 66 that exceeds the maximum linear dynamic range of the multiplier 63.
• the gain of the signal amplifier 70 that couples the output 66 of multiplier 63 collected on anode 67 to fast ADC 78, may also be adjusted by gain adjustment control 72 to ensure that the maximum signal in the spectrum does not exceed the maximum digitization range of the ADC 78.
• the gain of multiplier 63 of detector 50 may be adjusted by adjusting multiplier differential supply 68 to a high enough value to ensure that the greatest number of simultaneously arriving ions within a m/z spectrum does not produce a multiplier output signal 66 that exceeds the maximum linear dynamic range of the multiplier 63.
• the gain of the signal amplifier 70 that couples the output 66 of multiplier 63 collected on anode 67 to fast ADC 78, may also be adjusted by gain adjustment control 72 to ensure that the maximum signal in the spectrum does not exceed the maximum digitization range of the ADC 78.
• the gain of the other multiplier 83, and/or the gain of its associated amplifier 90 may be adjusted to higher levels than those of the multiplier 63 and/or amplifier 70 as described above, so that fewer simultaneously arriving ions produce the maximum ADC count of the ADC 198, than are necessary to produce the maximum ADC count of the ADC 78.
• gains for multipliers 83 and 63, and amplifiers 90 and 70 then, a fewer number of simultaneously arriving ions will produce a signal amplitude that is large enough to correspond to more than 1 count in the ADC, and therefore be detected, with detector 50 than are required with detector 51.
• the gain of multiplier 83 may be adjusted to values that are high enough to ensure that single ion hits 53 produce a signal amplitude at the input 173 of the ADC 198 that is great enough to correspond to at least several ADC counts. Single ion hits 53 may then be detected and measured with good efficiency with the detector 51. However, a greater number of simultaneously arriving ions at other m/z values may produce an output 86 from multiplier 83 with this multiplier gain, which may exceed either the linear dynamic range of the multiplier 83, and/or the maximum count of the ADC 198.
• multiplier 63 and/or its associated amplifier 70 may be operated at gain setting less than those of multiplier 83 and/or amplifier 90, such that the signal from a greater number of simultaneously arriving ions may be accommodated within the linear dynamic range of the multiplier 63, and within the count range of the ADC 78.
• the spectra from detector 50 may be integrated in integrating memory 80 while the spectra from detector 51 may be integrated in integrating memory 180.
• detector 50 consists of a dual channel electron multiplier plate assembly 63, which is comprised of two channel election multiplier plates 64 and 65 in series, so that, in response to the impact of ions 52, the first plate 64 produces an amplified output current which is further amplified by the second plate 65.
• An anode 67 collects the output current 66 of the second microchannel plate electron multiplier 65.
• the gain of the multiplier assembly is controlled by the voltage differential applied between the front surface of plate 64 and the back surface of plate 65. This voltage differential is provided by power supply 68.
• the output current 66 collected by anode 67 flows to the input 69 of amplifier 70.
• the gain of amplifier 70 is controlled by a reference voltage from gain control supply 72 provided at the gain control input 71 of amplifier 70.
• the amplified signal at the output of the amplifier 70 is provided to the input 110 of a fast analog switch 81.
• detector 51 in FIG. 5 consists of a dual channel electron multiplier plate assembly 83, which is comprised of two channel electron multiplier plates 84 and 85 in series, so that, in response to the impact of ions 53, the first plate 84 produces an amplified output current which is further amplified by the second plate 85.
• An anode 87 collects the output current 86 of the second microchannel plate electron multiplier 85.
• the gain of the multiplier assembly is controlled by the voltage differential applied between the front surface of plate 84 and the back surface of plate 85. This voltage differential is provided by power supply 88.
• the output current 86 collected by anode 87 flows to the input 89 of amplifier 90.
• the gain of amplifier 90 is controlled by a reference voltage from gain control supply 92 provided at the gain control input 91 of amplifier 90.
• the amplified signal at the output of the amplifier 90 is provided to a second input 111 of the fast analog switch 81.
• the control source 82 provides a control signal to the switch control input 112 of switch 81, said control signal which selects input 110 or input 111 to connect to the output 113 of fast switch 81.
• the output 113 is connected to the input 73 of a fast ADC 78.
• the fast ADC converts the analog signal to a sequence of digital values co ⁇ esponding to the amplitude of the signal as a function of time.
• the array of digital values therefore represents the time dependence of the ion flux arriving at the detector 50 or detector 51, depending on the state of fast switch 81 according to control source 82.
• a number of spectra from either detector 50 or detector 51 may be integrated in integrating memory 80, in order to improve the signal-to-noise and signal dynamic range of the spectrum, before being transferred to the memory of computer 101 for digital processing.
• the control source 82 in conjunction with fast switch 81 therefore allows a single fast ADC to be employed to integrate spectra from either detector 50 or detector 51, alternately.
• the spectral information from both detection systems may be integrated in the computer 101 in real time during data acquisition, or after data recording, to produce a composite integrated spectrum.
• FIG. 5 illustrates only two detectors configured this way, it should be understood that any number of detectors may be configured similarly within the scope of this embodiment of the present invention.
• FIG. 6 An alternative preferred embodiment of the present invention for the accumulation of spectra from either detector 50 or detector 51 is illustrated in FIG. 6.
• the configuration illustrated in FIG. 6 inco ⁇ orates two separate memory arrays, 80 and 116, for the integration of spectra, whereby memory array 80 accumulates spectra corresponding to the signal at detector 50, which, as described above, is amplified by amplifier 70, selected by switch 81, and digitized by fast ADC 78, while memory array 116 similarly accumulates spectra corresponding to the signal at detector 51 , which, as described above, is amplified by amplifier 90, selected by switch 81, and digitized by fast ADC 78.
• control signal from control source 82 that selects which detector's signal is digitized by fast ADC 78, is also applied to the integrating memory selection control input 114 of fast ADC 78. Therefore, when the signal from detector 50 is selected for digitization by fast ADC 78, the resulting digitized spectrum is integrated in accumulating memory 80, and when the signal from detector 51 is selected for digitization by fast ADC 78, the resulting digitized spectrum is integrated in accumulating memory 116.
• any number of spectra may be integrated for each detector, and in any sequence, before the integrated spectra in each histogram memory a ⁇ ay is transfe ⁇ ed to computer memory for further processing and possible integration into a composite spectrum.
• one spectrum may be measured and integrated in integrating memory associated with one detector, and then the next spectrum may be measured and integrated in integrating memory associated with the other detector, and so on, until the desired number of spectra are accumulated in both integrating memories.
• a number of spectra may be measured consecutively from one detector, and then a possibly different number of spectra may be integrated from the other detector, and so on with any desired sequence of integrations.
• FIG. 6 illustrates only two detectors configured this way, it should be understood that any number of detectors may be configured similarly within the scope of this embodiment of the present invention.
• FIG. 7 A further alternative a ⁇ angement for the implementation of a dual detector configuration is illustrated in FIG. 7.
• fast analog switch 81 is implemented to select the signal from one detector or the other before the signal is amplified.
• the signal from detector 50, collected on anode 67 is applied to input 110 of fast analog switch 81, while the signal from detector 51, collected on anode 87, is applied to input 111 of switch 81.
• Control source 82 provides an input select signal to input select control input 112 of fast analog switch 81, which selects the signal from either detector 50 or the signal from detector 51 to be routed to the output 113 of switch 81.
• the output 113 of switch 81 is connected to the input 69 of amplifier 70, which amplifies the signal with a gain that is controlled by gain control 72 via a control signal that gain control 72 applies to the gain control input 71 of amplifier 70.
• the amplifier output is then applied to the input 73 of fast ADC 78, which converts the analog signal to digital values that comprise the m/z spectrum.
• the same control signal from control source 82, that selects which detector's signal is routed to the amplifier 70, is also applied to the integrating memory selection control input 114 of fast ADC 78.
• the resulting digitized spectrum is integrated in accumulating memory 80 before being transfe ⁇ ed to computer memory
• the signal from detector 51 is selected for amplification by amplifier 70 and subsequent digitization by fast ADC 78
• the resulting digitized spectrum is integrated in accumulating memory 116 before being transfe ⁇ ed to computer memory.
• FIG. 8 Another prefe ⁇ ed embodiment of the present invention is illustrated in FIG. 8, and consists of two separate and independent detectors.
• One detector 50 consists of a dual channel electron multiplier plate assembly 63, which is comprised of two channel electron multiplier plates 64 and 65 in series, so that, in response to the impact of ions 52, the first plate 64 produces an amplified output cu ⁇ ent which is further amplified by the second plate 65.
• An anode 67 collects the output cu ⁇ ent 66 of the second microchannel plate electron multiplier 65.
• the gain of the multiplier assembly is controlled by the voltage differential applied between the front surface of plate 64 and the back surface of plate 65. This voltage differential is provided by power supply 68.
• the output cu ⁇ ent 66 collected by anode 67 flows to the input 69 of amplifier 70.
• the gain of amplifier 70 is controlled by a reference voltage from gain control supply 72 provided at the gain control input 71 of amplifier 70.
• the amplified signal at the output of the amplifier 70 is provided to the input 73 of a fast analog-to-digital converter 78, which converts the analog signal to a sequence of digital values co ⁇ esponding to the amplitude of the signal as a function of time.
• the a ⁇ ay of digital values therefore represents the ion flux arriving at the detector 50 as a function of time, which is easily inte ⁇ reted as the m/z spectrum of ions in the ion population.
• a number of such spectra may be integrated in integrating memory 80, in order to improve the signal-to-noise and intensity dynamic range of the spectrum, before being transfe ⁇ ed to the memory of computer 101 for digital processing.
• a second detector 51 consists of a dual channel electron multiplier plate assembly 83, which is comprised of two channel electron multiplier plates 84 and 85 in series, so that, in response to the impact of ions 53 A, 53B, 53C, etc., the first plate 84 produces an amplified output cu ⁇ ent which is further amplified by the second plate 85.
• This second detector 51 is configured with a multiplicity of collector anodes, anode 87A, anode 87B, anode 87C, etc., which collect the co ⁇ esponding output cu ⁇ ents 86A, 86B, 86C, etc., respectively, of the second microchannel plate electron multiplier 85, resulting from the impact of ions 53A, 53B, 53C, etc., respectively.
• the gain of the multiplier assembly is controlled by the voltage differential applied between the front surface of plate 84 and the back surface of plate 85. This voltage differential is provided by power supply 88.
• the amplified signals at the outputs of the amplifiers 90B, 90C, etc. are provided to the inputs 93B, 93C, etc., of discriminators 94B, 94C, etc., which compare the amplitudes of the signals at inputs 93B, 93C, etc., with the amplitudes of reference levels provided at threshold reference inputs 95B, 95C, etc., which are adjusted by threshold reference adjustment supplies 95B, 95C, etc., respectively.
• the gain of the other multiplier 83, and/or the gain of its associated amplifier 70B may be adjusted to higher levels than those of the multiplier 63 and/or amplifier 70 A, so that fewer simultaneously arriving ions produce the maximum ADC count of the ADC 78B, than are necessary to produce the maximum ADC count of the ADC 78 A.
• gains for multipliers 83 and 63, and their respective amplifiers 70B and 70 A then, a fewer number of simultaneously arriving ions will produce a signal amplitude that is large enough to co ⁇ espond to more than 1 count in the ADC, and therefore be detected, with detector 50 than are required with detector 51.
• Single ion hits may be recorded with detector 51 by utilizing the TDC's 98B, 98C, etc. as described above.
• the gains of amplifiers 90B, 90C, etc. may be increased by adjusting the reference voltage from gain control supplies 92B, 92C, etc. provided at the gain control inputs 9 IB, 91C, etc. of amplifiers 90B, 90C, etc., respectively.
• the spectral information from all anodes coupled to TDC acquisition systems within all detectors may be combined, and, for those ion m/z values with intensities low enough to allow valid single-ion counting with a TDC, a ⁇ ival times may be measured with greater precision and accuracy with the TDC's 98A, 98B, 98C, etc., than with typical fast ADC's 78A and 78B, resulting in improved m/z ToF resolving power and measurement accuracy for those low-intensity ions in the resulting integrated spectrum.
• the multiple anodes and TDC acquisition systems provide extended dynamic range for low-amplitude signals relative to a single anode and TDC acquisition system.
• the gains of the amplifiers coupling the other anodes to the ADC acquisition systems may be reduced, thereby extending the range of signal amplitudes that may be measured by the ADC acquisitions to greater signal amplitudes, because the ADC acquisition systems would not need to record the low-amplitude signals that are recorded by the multiple TDC acquisition systems.
• the overlap in dynamic range between the TDC acquisition systems and the ADC acquisitions allows a cross-calibration between these two types of acquisition systems with respect to signal amplitude and time scale.
• the greater time precision of the TDC approach may provide better arrival time information even for the simultaneous arrival of multiple ions at other m/z values than the fast ADC acquisition systems, thereby enhancing the precision and accuracy of all measured m/z values.
• this embodiment of the present invention allows both single-ion and multiple-ion amplitude information, obtained from multiple detectors coupled to multiple ADC and multiple TDC acquisition systems, to be combined with the more precise arrival time information and better signal-to-noise of the TDC acquisition systems, the result being that m/z ToF spectra may be produced with greater dynamic range, time resolution, and signal-to-noise than is possible with the prior art detection systems.
• FIG. 9 illustrates only two detectors configured this way, it should be understood that any number of detectors may be configured similarly within the scope of this embodiment of the present invention.
• the number of spectra integrated by one detector can be different from the number of spectra integrated by the other detector, for example detector 51 in FIG. 6.
• detector 51 is employed to measure low intensity m/z peaks with relatively high gain
• detector 50 is employed to measure high intensity m/z peaks with relatively low gain
• the resulting signal-to-noise will be improved if the total number of integrated spectra in the composite spectrum is divided unequally between the two detectors such that number of spectra integrated from detector 51 is greater than that from detector 50.

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